2Z7H: S. Cerevisiae Geranylgeranyl Pyrophosphate Synthase In Complex With Inhibitor Bph-210

Citation:
Abstract
We report the X-ray crystallographic structures of the bisphosphonate N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (BPH-210), a potent analog of pamidronate (Aredia), bound to farnesyl diphosphate synthase (FPPS) from Trypanosoma brucei as well as to geranylgeranyl diphosphate synthase from Saccharomyces cerevisiae. BPH-210 binds to FPPS, together with 3 Mg(2+), with its long, hydrophobic phenylbutyl side-chain being located in the same binding pocket that is occupied by allylic diphosphates and other bisphosphonates. Binding is overwhelmingly entropy driven, as determined by isothermal titration calorimetry. The structure is of interest since it explains the lack of potency of longer chain analogs against FPPS, since these would be expected to have a steric clash with an aromatic ring at the distal end of the binding site. Unlike shorter chain FPPS inhibitors, such as pamidronate, BPH-210 is also found to be a potent inhibitor of human geranylgeranyl diphosphate synthase. In this case, the bisphosphonate binds only to the GGPP product inhibitory site, with only 1 (chain A) or 0 (chain B) Mg(2+), and DeltaS is much smaller and DeltaH is approximately 6 k cal more negative than in the case of FPPS binding. Overall, these results are of general interest since they show that some bisphosphonates can bind to more than one trans-prenyl synthase enzyme which, in some cases, can be expected to enhance their overall activity in vitro and in vivo.
PDB ID: 2Z7HDownload
MMDB ID: 64307
PDB Deposition Date: 2007/8/23
Updated in MMDB: 2008/09
Experimental Method:
x-ray diffraction
Resolution: 2.08  Å
Source Organism:
Similar Structures:
Biological Unit for 2Z7H: dimeric; determined by author and by software (PISA)
Molecular Components in 2Z7H
Label Count Molecule
Proteins (2 molecules)
2
Geranylgeranyl Pyrophosphate Synthetase(Gene symbol: BTS1)
Molecule annotation
Chemicals (3 molecules)
1
1
2
2
* Click molecule labels to explore molecular sequence information.

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